Hydroxylation of benzo[a]pyrene and binding of (-)trans 5-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene metabolites to deoxyribonucleic acid catalyzed by purified forms of rabbit liver microsomal cytochrome P-450 : Effect of 7,8-benzoflavone, butylated hydroxytoluene and ascorbic acid
Belvedere, Giorgio; Miller, Haruko; Vatsis, Kostas P.; Coon, Minor J.; Gelboin, Harry V.
1980-06-15
Citation
Belvedere, Giorgio, Miller, Haruko, Vatsis, Kostas P., Coon, Minor J., Gelboin, Harry V. (1980/06/15)."Hydroxylation of benzo[a]pyrene and binding of (-)trans 5-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene metabolites to deoxyribonucleic acid catalyzed by purified forms of rabbit liver microsomal cytochrome P-450 : Effect of 7,8-benzoflavone, butylated hydroxytoluene and ascorbic acid." Biochemical Pharmacology 29(12): 1693-1702. <http://hdl.handle.net/2027.42/23220>
Abstract
The catalytic activities of hepatic microsornes from untreated, phenobarbital-treated and 3-methylcholanthrene-treated adult rabbits with respect to benzo[a]pyrene hydroxylation and the activation of (-)(rflw-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene[(-)trans-7,8-diol] to DNA-binding metabolites were determined in the absence and presence of mixed-function oxidase inhibitors and compared to the corresponding activities of the individual enzyme systems. Treatment of rabbits with phnobarbital led to induction of P-450LM2 and a concomitant 3-fold enhancement in microsomal benzo[a]pyrene hydroxylase activity, whereas the conversion of (-)trans-7,8-diol to DNA-binding products was unaffected. Homogeneous phenobarbital-inducible P-450LM2 exhibited the highest activity and specificity toward benzo[a]pyrene and the lowest activity toward (-)trans-7,8-diol. Conversely, P-450LM4 was the major form of cytochrome P-450 induced in rabbit liver by 3-methylcholanthrene or [beta]-naphthoflavone, and this was associated in microsomes with an increase in the metabolism of (-)trans-7, 8-diol but not of benzo[a]pyrene. Homogeneous P-450LM4 preferentially Catalyzed the oxygenation of (-)trans-7,8-diol, but was largely ineffective with benzo[a]pyrene. Partially purified P-450LM7 lacked substrate specificity, for it metabolized both benzo[a]pyrene and (-)trans-7, S-diol at comparable rates. Additionally, 7,8-benzoflavone strongly inhibited benzo[a]pyrene hydroxylation by P-450LM4 and phenobarbital-induced microsomes, as well as (-)trans-7,8-diol metabolism by P-450LM4 and 3-methyl-cholanthrene-induced microsomes; in contrast, the activity of control microsomes with either substrate, and the activities of P-450LM4 and LM2 with benzo[a]pyrene and (-)trans-7 ,8-diol, respectively, were only partially or slightly decreased by 7,8-benzoflavone. Unlike 7,8-benzoflavone, butylated hydroxytoluene inhibited benzo[a]pyrene hydroxylation only. Thus, different forms of rabbit liver microsomal cytochrome P-450 were involved in the metabolism of benzo[a]pyrene and its 7,8-dihydrodiol. The results also demonstrate that the changes in substrate specificity and inhibitor sensitivity seen in phenobarbital- and 3-methylcholanthrene-induced microsomes relative to control rabbit liver microsomes can be accounted for by the catalytic properties of a specific form of cytochrome P-450 that prevails in these preparations, P-450LM2 and LM4, respectively.Publisher
Elsevier
PMID
7190824
Types
Article
URI
http://www.sciencedirect.com/science/article/B6T4P-474YKSX-DN/2/f9abffbebe21a0736bfa044ca7118c4chttp://www.ncbi.nlm.nih.gov/sites/entrez?cmd=retrieve&db=pubmed&list_uids=7190824&dopt=citation
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